A preeminent role of early adverse experiences in the pathogenesis of psychiatric disorders has long been postulated and has been supported by recent studies. We hypothesize~that early adverse experiences may induce an increased sensitivity to the effects of stress later in life and render an individual vulnerable to stress-related psychiatric disorders. This vulnerability may be mediated by persistent changes in corticotropin- releasing factor (CRF)-containing neurons and the hypothalamic-pituitary- adrenal (HPA) axis as well as noradrenergic and serotonergic neurotransmitter systems. In this project, we will characterize neurobiological consequences of early adverse experiences, i.e. childhood sexual and/or physical abuse. Specifically, we will compare indices of central CRF activity, HPA axis function, noradrenergic and serotonergic neuronal activity as well as sympathetic-nervous system activity, and structural alterations in several brain regions in women with a personal history of childhood abuse (early life stress, ELS) and current major depression (ELS/MDD), women with a history of childhood abuse without major depression (ELS/non-MDD), women without a history of childhood abuse and major depression (non-ELS/MDD) and women without a history of childhood abuse and no psychiatric disorder (CONTROLS). Based on our findings in animal models, we also will evaluate whether the profound neuroendocrine consequences of early life stress are reversed "by treatment with the selective serotonin reuptake inhibitor, fluoxetine. Using structural MRI methods, the volume of the hippocampus will be compared in the four diagnostic groups. In collaboration with the functional brain imaging core, these subjects will participate in studies to measure CNS density of both the serotonin transporter and the CRF1 receptor, as well as fMRI measures of stress reactivity. Findings from this project will increase our understanding of the pathogenesis of psychiatric disorders and will help to develop new intervention strategies to prevent adulthood psychopathology in victims of childhood abuse.